Nonclinical Strategies for Refining Combination Rectal Formulations

面对目前的艾滋病毒-1流行病，需要采取有效的预防方式组合，以开始 减少HIV-1的发病率。这包括使用局部杀微生物剂。这些产品将会 用于预防艾滋病毒-1的性传播；包括接受性肛交。项目1， 本U19将努力确保精制组合直肠制剂的非临床策略 将开发安全有效的直肠杀菌剂。迄今为止，“第一代”的2b阶段试验 杀微生物剂产品，壬醇-9，SAVY，硫酸纤维素和CarraGuard，都没有显示出 有效或显示出危害，并被提前停止。这导致了使用“第二代”的方式。 包括抗逆转录病毒(ARV)药物UC781和替诺福韦的杀微生物剂产品。我们有 开发了一种创新的测试算法来评估ARV直肠杀菌剂的安全性和有效性 (Rm)将由该U19(核心C)开发的配方。这包括使用极化的结直肠 外植体培养系统，到目前为止已经产生了反映非人灵长类动物的结果 和人类阶段1临床安全数据以及对非人灵长类和人类阶段2b的预测 临床疗效数据。有兴趣确定这些RM配方是否有效地独立于 性交以及在精液存在的情况下。最后，在预期开发组合的 杀微生物剂将具有多种作用机制来提高预防效果，分子 阻断或阻止HIV-1与靶细胞融合的药物将接受测试，以确定与 抗逆转录病毒药物。这项工作的最终目标是确保在此U19中为RM开发的内容将是 安全，在临床试验中测试时具有高度有效性的潜力。

In the face of the existing HIV-1 epidemic, an effective mix of prevention modalities are needed to begin to reduce the incidence of HIV-1. This includes the used of topical microbicides. These are products that would be used to prevent the sexual transmission of HIV-1; including receptive anal intercourse. Project 1, Nonclinical Strategies for Refining Combination Rectal Formulations, of this U19 will strive to ensure that a safe and effective rectal microbicide will be developed. To date, the Phase 2b trials of "first generation" microbicide products, nonoxynol-9, SAVVY, cellulose sulfate, and Carraguard, have either failed to show effectiveness or showed harm and were halted early. This has lead the way to using "second generation" microbicide products that encompass the antiretroviral (ARV) drugs, UC781 and tenofovir. We have developed an innovative testing algorithm to evaluate safety and effectiveness of ARV rectal microbicide (RM) formulations that will be developed by this U19 (Core C). This includes the use of a polarized colorectal explant culture system which to date has generated results that has been reflective of nonhuman primate and human Phase 1 clinical safety data as well as predictive of nonhuman primate and human Phase 2b clinical effectiveness data. It is of interest to determine if these RM formulations are effective indepentent of coitus as well as in the presence of semen. Finally, in anticipation of developing combinations of microbicides that will have multiple mechanisms of action to improve preventative effectiveness, molecules that block or prevent the fusion of HIV-1 with the target cell will be tested for antagonism or synergy with the ARV drugs. The ultimate goal of this work will be to ensure that what is developed in this U19 for RM will be safe and have the potential to be highly effective when tested in a clinical trial.